Safety and Efficacy Dabigatran vs Rivaroxaban_deposit_UoL

Key words atrial fibrillation; rivaroxaban; dabigatran; warfarin; real-world data Abstract Background and Purpose: This study was designed to evaluate the effectiveness and safety 1... o

Rivaroxaban vs Dabigatran or warfarin in ‘real-world’ studies of stroke prevention in atrial fibrillation: Systematic review and meta-analysis

Ying Bai, PhD a,b , Hai Deng, PhDa,c, Alena Shantsila, PhDa, Gregory Y H Lip, MD, FRCP a,d

a University of Birmingham, Institute of Cardiovascular Sciences, City Hospital, BirminghamB18 7QH, United Kingdom;

b Cardiovascular Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China;

c Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy ofMedical Science, Guangzhou, China;

dAalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University,Aalborg, Denmark

Corresponding author:

Professor GYH Lip

University of Birmingham Institute of Cardiovascular Sciences, City Hospital, BirminghamB18 7QH, United Kingdom

Tel: +44 121 507 5080; Fax: +44 121 507 5503; E-mail: g.y.h.lip@bham.ac.uk

Number of tables 2, Number of figures 4

Key words atrial fibrillation; rivaroxaban; dabigatran; warfarin; real-world data

Abstract

Background and Purpose: This study was designed to evaluate the effectiveness and safety

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of rivaroxaban in real-world practice compared with dabigatran or with warfarin for strokeprevention in atrial fibrillation (AF) through meta-analyzing observational studies.

Methods 17 studies were included after searching in PubMed for studies reporting the

comparative effectiveness and safety of rivaroxaban vs dabigatran(n=3), rivaroxaban vs.warfarin(n=11) or both(n=3) for stroke prevention in AF

Results: Overall, the risks of stroke/systematic thromboembolism (TE) with rivaroxaban were

similar compared with dabigatran [Stroke/TE:(1.02, 0.91-1.13, I2=70.2%, N=5)], but weresignificantly reduced when compared to warfarin (0.75,0.64-0.85, I2=45.1%, N=9) Majorbleeding risk was significantly higher with rivaroxaban than dabigatran (1.38, 1.27-1.49,

I2=26.1%, N=5), but similar to warfarin (0.99, 0.91-1.07, I2=0.0%, N=6) Rivaroxaban wasassociated with increased all-cause mortality and gastrointestinal bleeding (GIB), but similarrisk of acute myocardial infarction (AMI) and intracranial hemorrhage (ICH) compared withdabigatran When compared with warfarin, rivaroxaban was associated with similar risk ofany bleeding, mortality and AMI, but a higher risk of GIB and lower risk of ICH

Conclusions: In this systematic review and meta-analysis, rivaroxaban was as effective as

dabigatran, but was more effective than warfarin for the prevention of Stroke/TE in AFpatients Major bleeding risk was significantly higher with rivaroxaban than dabigatran, aswas all-cause mortality and GIB Rivaroxaban was comparable to warfarin for majorbleeding, with an increased risk in GIB and decreased risk of ICH

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The use of oral anticoagulants (OACs) such as the Vitamin K antagonists (VKA, eg warfarin)

in patients with atrial fibrillation (AF) results in a significant reduction in stroke, ischemicstroke (IS) and systematic thromboembolism (TE), as well as all-cause mortality, whencompared to placebo or control.1 However, warfarin has many limitations, including thenecessity for regular anticoagulation monitoring, dietary and drug interactions, and thepotential for serious bleeding if anticoagulation is poorly controlled, as reflected by a poortime in therapeutic range (TTR).2

The availability of the non-vitamin K antagonist oral anticoagulants (NOACs) have changedthe landscape for stroke prevention in AF, and a meta-analysis of randomized clinical trials(RCTs) by Ruff et al 3 has shown that usual dose NOACs result in a significant reduction instroke/TE and mortality with NOACs compared to warfarin, with a trend towards less majorbleeding and significantly lower intracranial hemorrhage (ICH) However, RCTs have specificinclusion/exclusion criteria, set protocol-based follow-up and perhaps represent a highlyselected and controlled scenario, but still represent the gold standard of testing theeffectiveness and safety of an intervention Based on RCT data, indirect comparisons havebeen published showing how the different NOACs may perform relative to each other 4, 5 butonly a head-to-head RCT can definitively assess the relative efficacy and safety of one NOACagainst another

When a drug is licensed and used in everyday clinical practice, these drugs are then used in a

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broad patient population beyond the RCTs.6 Since the publication of the RCT data andregulatory approval of these drugs (rivaroxaban and dabigatran), numerous real worldobservational cohorts showing the comparative effectiveness and safety of the NOACs havebeen published.7-12 Our objective was to perform a systematic review and meta-analysis ofdata on the effectiveness and safety of rivaroxaban in real-world practice compared withdabigatran or with warfarin for stroke prevention in AF.

Methods

We followed the preferred reporting items for systematic reviews and meta-analyses(PRISMA) and the reporting Meta-analyses of Observational Studies in Epidemiology(MOOSE) when performing this meta-analysis.13, 14

Two independent reviewers (Y B and H D.) conducted a search of Medline and theCochrane Library using the following items “atrial fibrillation”, “AF”, “rivaroxaban”,

“dabigatran”, “warfarin”, “real-world”, “observational studies” until 4 October, 2016,respectively We also reviewed the lists of references in eligible studies and reviews.Disagreement was resolved by consensus

To be included in the meta-analysis, the observational studies needed to fulfill the followingcriteria: (i) With OACs used for stroke prevention in patients with AF; (ii) Availablequantitative data on clinical events; (iii) Adjusted hazard ratios (HRs) between rivaroxaban

vs dabigatran, or rivaroxaban vs warfarin for stroke prevention in AF The following studies

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were excluded:

(i) Animal based studies;

(ii) Non-English based papers;

(iii) Abstracts, editorials, case-reports, reviews and case series;

(iv) Specific studies on AF patients undergoing ablation or cardioversion

We recorded clinical events related to effectiveness outcomes as IS, TE, the combination ofStroke and TE (Stroke/TE), and acute myocardial infarction (AMI) of rivaroxaban incomparison with dabigatran or warfarin Separate IS, hemorrhagic stroke, stroke or TEoutcomes were used instead if no data on Stroke/TE was available in the original papers.Safety outcomes were major bleeding, any bleeding, ICH, gastrointestinal bleeding (GIB) orall-cause mortality Definitions of these effectiveness and safety outcomes were extractedfrom the original papers If available, other collected study characteristics included: authors,publication year, study country, period, cohort size, percentage of low-dose rivaroxaban,percentage of low-dose dabigatran, new-users or switchers of NOACs and estimated follow-

up duration Quality score for each study was assessed by the Newcastle-Ottawa scale.15

Statistical analysis

The analysis was conducted using STATA, version 12.0 (Stata Corp.) Event rate of variousoutcomes were evaluated using count of events/person-years of observation Adjusted HRswith 95% confidence intervals (95% CI) was used to measure the effect sizes in our study.First we used a fixed model, and then a random effects model if there was heterogeneity

according to I 2 index 16 Values of ≤25%, 25-50%, and ≥50% were defined as low, moderateand high degrees of heterogeneity, respectively Begg’s correlation test and Egger’s

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regression test were used to assess publication bias.17-19 Sensitivity analyses were performed

in dose-categorized comparisons of NOACs and ‘new user/switcher’ settings P<0.05 wastaken as statistically significant

Results

A total of 1086 studies were initially identified (including 829 on-line and 257 fromreferences) After screening titles and abstracts, we excluded 1007 papers and 79 remainedfor a detailed evaluation Of these studies, 62 were excluded as they did not meet theinclusion criteria (6 were reviews and meta-analysis; 25 studies on OACs in specific AFpopulations, such as ablation or cardioversion were excluded due to their modest size andshort period of follow-up (less than 30 days) Also, 12 papers lacked outcome data in AFpatients Comparison of separate data for rivaroxaban with warfarin could not be extractedfrom 2 papers; adjusted HRs between OACs comparisons were lacking in 16; and no separate

AF data could be extracted from 1 paper with mixed disease states Finally, 17 observationalstudies7-12, 20-31 were included in our analysis, with 3 comparing rivaroxaban vs dabigatran9-11,

11 comparing rivaroxaban vs warfarin20-27, 29-31 and 3 evaluating both comparisons7, 8, 12

Studies with new users and switchers are shown in Supplementary Table I Quality scoring revealed moderate-to-high scores of the included studies The selection process and baseline characteristics of included studies are summarized in Supplementary Figure I and Tables 1 and 2 Anticipated outcomes evaluated are summarized in Supplementary Table II The endpoints in various comparison settings are shown in Supplementary Table III.

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Comparisons between Rivaroxaban and Dabigatran

Rivaroxaban was associated with a similar risk of Stroke/TE compared with dabigatran,

7-11(HR: 1.02, 95% CI: 0.91-1.13, I2=70.2%, N=5) (Figure 1), with pooled rates for rivaroxaban

being 0.3%/year vs dabigatran 0.3%/year No significant publication bias was seen amongthe included studies using Begg’s test (p=0.21) and Egger’s test (p=0.25) Subanalysis wasperformed through pooling 3 studies evaluating the IS risk between rivaroxaban anddabigatran9-11, which was non-significantly different, (HR: 0.98, 95% CI: 0.88-1.08, I2=46.0%,

p=0.12), (Supplementary Figure II), with pooled rates for rivaroxaban being 0.57%/year vs.

dabigatran 0.54%/year No significant publication bias was seen among the included studiesusing Begg’s test (p=0.46) and Egger’s test (p=0.08)

The pooled rate of major bleeding was 1.45%/year for rivaroxaban and 0.55%/year fordabigatran Major bleeding risk was significantly higher with rivaroxaban than dabigatranafter pooling the five studies.7, 9-12 (HR: 1.38, 95% CI: 1.27-1.49, I2=26.1%, N=5) (Figure 2) No

significant publication bias was seen among the included studies using Begg’s test (p=0.76)and Egger’s test (p=0.39)

Rivaroxaban was associated with increased risk in all-cause mortality7-10 (HR: 1.23, 95% CI:1.12-1.33, I2=31.5%, N=4), any bleeding8-10 (HR:1.33, 95% CI:1.17-1.49, I2=74.8%, N=3) andGIB7, 9, 10 (HR: 1.33, 95% CI: 1.18-1.48, I2=58.3%, N=3), but similar risk of AMI7, 9 (HR: 0.81, 95%CI: 0.43-1.19, I2=0.0%,N=2) and ICH7, 9-11 (HR: 1.22, 95% CI: 0.85-1.59, I2=64.5%,N=4) whencompared with dabigatran

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Comparisons between Rivaroxaban and Warfarin

The pooled annual rate of Stroke/SE was 2.57%/year for rivaroxaban and 2.86%/year forwarfarin in AF patients (HR: 0.75, 95% CI: 0.64-0.85, I2=45.1%, N=9).7, 8, 21, 22, 25, 26, 29-31 (Figure 3) Subgroup analysis was performed through meta-analyzing 6 observational studies

evaluating IS risk between rivaroxaban and warfarin20, 22, 25, 26, 30, 31, and rivaroxaban wasassociated with lower risk of IS (HR: 0.86, 95% CI: 0.75-0.97, I2=0.0%, N=6) (Supplementary Figure III) No publication bias was seen according to Begg’s test (IS: p=1.0; Stroke/SE:

p=0.37) and Egger’s test (IS: p= 0.87; Stroke/SE: p=0.1)

The pooled rate of major bleeding was 3.70%/year for rivaroxaban and 3.73%/year forwarfarin, based on meta-analysis of 6 studies (HR:0.99, 95% CI: 0.91-1.07, I2=0.0%, N= 6).7, 12, 24-26, 30 (Figure 4) No publication bias were seen in this study according to Begg’s test (p=0.26)

and Egger’s test (p=0.22)

Rivaroxaban was associated with similar risk of any bleeding (HR:1.01, 95% CI: 0.94-1.08,

I2=0.0%, N=5)8, 21, 24, 26, 29, AMI (HR: 0.73, 95% CI: 0.30-1.15, I2=0.0%, N=2)7, 21 and all-causemortality (HR: 1.04, 95% CI: 0.64-1.44, I2=92.7%, N=3) 7, 8, 26 compared with warfarin The risk

of ICH was significantly lower (HR: 0.54, 95% CI: 0.43-0.64, I2=63.6%, N=6)7, 22, 24-26, 30, but risk

of GIB was significantly higher (HR: 1.2, 95% CI: 1.07-1.33, I2=27.5%, N=5)7, 20, 24, 25, 30 withrivaroxaban compared to warfarin

Sensitivity Analysis

The results were consistent among studies for both low-dose and high-dose rivaroxaban vs

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dabigatran comparisons on the clinical outcomes, except for the endpoint of AMI, where

studies did not report on low-dose rivaroxaban vs dabigatran comparisons (Supplementary Figure IV).

The risk of Stroke/TE was similar (1.08, 0.95-1.21, I2=70.7%, N=4)7-10 when we conductedsensitivity analysis including studies with NOAC (Rivaroxaban vs Dabigatran) new-users.When sensitivity analysis was performed for new-users of rivaroxaban vs warfarin, therewas general consistency with the summary comparisons Although new users of rivaroxabanshowed significant reductions in IS (HR 0.85, 0.72-0.97), Stroke/TE (0.78, 0.69-0.87) and ICH(-0.64,0.51-0.77) No significant difference in major bleeding, any bleeding, mortality and

GIB was evident amongst new users (Supplementary Figure V, Table I and Table III).

For other endpoints, the results were broadly similar with the summary analysis except for

an increased risk of mortality in low-dose rivaroxaban and similar risk of IS in high-dose

rivaroxaban, when compared with warfarin (Supplementary Figure VI).

To minimize any confusion, we also show numbers needed to treat and numbers needed toharm were calculated for the absolute effectiveness and safety comparison

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Our results are partially discordant from previous indirect comparisons of R vs D for the risk

of Stroke/TE and major bleeding in AF patients.4, 5 The large randomized trials32 33 differed ininclusion criteria based on stroke risk profile Bias could easily be produced with unadjustedconfounding, which was considered but unresolved in previous indirect comparisonanalyses In contrast, our included ‘real-world’ studies have used adjusted HRs andcompared subjects with broadly similar stroke risks taking rivaroxaban or dabigatran duringthe same time period within each study

Different percentages of patients received low-dose NOACs in the published real-worldstudies (eg for low-dose rivaroxaban and dabigatran: nearly 90% in Hernandez et al,10 andabout 30% in Chan et al7) However, there were generally consistent results between low-dose and high-dose rivaroxaban vs dabigatran in most clinical outcomes

Our findings provide an estimate of the various anticipated outcomes of rivaroxaban whenused in everyday clinical practice when compared to warfarin Rivaroxaban was a non-inferior alternative to warfarin in IS, Stroke/TE prevention While the results were similar tothe summary data, low-dose and high-dose rivaroxban vs warfarin data were limited when

the sensitivity analysis was done Our results also provide some insights regarding whether

to switch patients from warfarin to NOACs Rivaroxaban new-users showed superioreffectiveness to warfarin for IS and Stroke/TE prevention, but switchers showed similar risks.The exact reason(s) are unknown, but could be partly explained by the assumption of poorcompliance for OACs in those switched from warfarin, because usually AF patients would betransferred to take rivaroxaban for poor TTR of warfarin Importantly, our study reflects real-world clinical practice, given that patients included in ROCKET-AF had a higher stroke riskprofile.33

In safety evaluations, both ROCKET-AF33 and our analysis have shown patients treated withrivaroxaban have increased GIB risk and decreased ICH risk compared to warfarin Anancillary analysis of ROCKET-AF has ascribed the higher GIB to a history of GIB or older age.34Our results could partially provide supportive evidence for this hypothesis, as newrivaroxaban users had a similar risk of GIB compared with warfarin users, with GIB riskevaluated using HRs adjusted for age and bleeding history, within the included studies.20, 24ICH is the most feared complication for OACs and consistent with trial data, we show thatrivaroxaban users had significantly less ICH compared to warfarin

Limitations and Strengths

To our knowledge, this is the first meta-analysis of the head-to-head comparison amongNOACs There are several limitations inherent to the interpretation of these results First,only studies in English were included for the analysis which increased the potential languagebias However, a tendency towards publication in English journals minimized this effect.35Second, high heterogeneity across studies in Stroke/TE should not be neglected, though arandom-effects model was used for adjustment Nonetheless, results were broadly similareven if sensitivity analysis (eg new-users or different dose prescription) and subgroupanalysis in IS, which decreased the heterogeneity, were performed Third, differentinclusion/exclusion criteria and follow-up periods in the included studies led to highheterogeneity, so it is necessary to cautiously interpret the noticeable differences in someevent rates between the rivaroxaban vs dabigatran cohort, and rivaroxaban vs warfarincomparisons (eg Stroke /TE rate 0.3%/year in the former vs 2.8%/year in the latter; majorbleeding was 1.45%/year in the former vs 3.89%/year in the latter) To provide someperspective, we also show numbers needed to treat and numbers needed to harm for the

absolute effectiveness and safety comparisons in Supplementary Table IV Fourth, inherent

limitations in the majority of meta-analysis, such as lack of access to raw data and thevariety in definitions of outcomes in the included studies are unavoidable However, we haveenhanced the robustness of the analysis through extracting the effect sizes with adjustedHRs from the original studies Indeed, low heterogeneity in the safety evaluations enhancesthe clinical applicability of our observations No publication bias and the moderate-to-highquality scores according to Newcastle-Ottawa scale both increase the reliability of the

pooled estimate Finally, the analysis covers the whole population of AF patients and noseparate outcome information could be extracted for some subgroups, eg patients with TIA

or prior stroke

Conclusions

In this systematic review and meta-analysis, rivaroxaban was as effective as dabigatran forthe prevention of IS and Stroke/TE, but was more effective than warfarin for strokeprevention in AF patients Major bleeding risk was significantly higher with rivaroxaban thandabigatran, as was all-cause mortality and GIB Rivaroxaban was comparable to warfarin formajor bleeding, with an increased risk in GIB and decreased risk of ICH

Hence, the risks and benefits of rivaroxaban use should be carefully accounted for, especiallythe individual’s risk of GIB Based on the real-world evidence up to date, rivaroxaban was notsuperior to dabigatran for stroke prevention in AF patients, but had more bleeding risks

Sources of Funding: None This work was conducted independent of any industry

collaboration or sponsorship

Conflicts of Interest/Disclosures: GYHL has served as a consultant for Bayer/Janssen,

BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Microlife and Daiichi-Sankyo.Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche andDaiichi-Sankyo Other authors: None declared

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Table 1 Baseline characteristics in Rivaroxaban versus Dabigatran studies

Author, year Region Enrolled Period Cohort size LD-R(%) LD-D(%) eFollow-up

Gorst-Rasmussen, 20168 Denmark Feb, 2012-Jul, 2014 113,13 32.3 40.3 1.08 y

HD-D, high-dose dabigatran; HD-R: high-dose rivaroxaban; LD-D, low-dose dabigatran; LD-R, low-dose rivaroxaban; eFollow-up, estimated follow-up; y, years ;NA, not available

Table 2 Baseline Characteristics in Rivaroxaban versus Warfarin studies